IGF-II regulation of FABPs in the breast cancer survival disparity among AA women

描述（由申请人提供）：有充分的证据表明，非裔美国人（AA）患者表现为更晚期的乳腺癌（BC），其生存率低于白人美国人（CA）。这种差异部分是由社会经济因素造成的；然而，社会和环境因素的相互作用也可以调节生物因素。一个典型的例子就是哺乳对女性预防乳腺癌的保护作用。一些研究表明，社会因素、种族、民族差异和社会经济地位如何影响母亲母乳喂养的开始、频率和持续时间。这些因素也会影响母亲决定是否母乳喂养以及母乳喂养的时间。流行病学数据表明，早期怀孕和哺乳可以降低患乳腺癌的风险。然而，这种对人类的保护作用的机制尚不清楚。对小鼠和大鼠的研究表明，哺乳刺激细胞内脂肪酸结合蛋白（FABPs）的表达。不同的FABPs（1-9）在心脏、脑、肝等特定组织中表达。泌乳大鼠乳腺组织中FABP3表达显著升高，其表达调节泌乳启动的保护作用。人类乳腺组织中也检测到FABP3，由于其对细胞增殖具有很强的抑制作用，因此被称为乳腺源性生长抑制剂（MDGI）。另外，我们也很清楚地知道，fabp具有一种代偿关系，即当y-FABP降低时，x-FABP水平会升高。因此，由于FABP3抑制乳腺细胞增殖，我们推断该蛋白在乳腺组织中的差异表达与乳腺癌的进展有关。因此，我们假设AA女性的FABP3水平较低，因为AA女性的泌乳率在CA、西班牙裔（HA）和亚裔美国女性中最低。同样，我们推断，在AA女性的组织中，FABP5水平（也在乳腺中检测到）会更高，以弥补FABP3的下降。因此，我们建议评估这些FABPs在AA和CA配对的正常/肿瘤BC组织中的表达（来自人类合作组织网络），以确定AA女性中FABP3的低表达/ FABP5的高表达是否与AA和CA BC患者之间观察到的BC进展差异有关。为了表征与FABP3和FABP5调控相关的潜在机制，我们还将使用从ATCC获得的CA和AA患者建立的细胞系。采用免疫印迹法、Elisa法和共聚焦免疫荧光法检测FABPs蛋白水平。采用定量rt-PCR检测mRNA水平。由于泌乳是由催乳素和IGF-II调节的，我们也将确定这些蛋白如何调节FABPs和从AA和CA女性建立的BC细胞系的细胞分化。如果成功，我们的研究将为哺乳对乳腺的保护作用提供必要的信息，并有可能为预防性乳腺癌治疗提供新的工具。

DESCRIPTION (provided by applicant): It is well documented that African-American (AA) patients present with more advanced states of breast cancer (BC) and have lower survival rates than Caucasian-Americans (CA). Some of this disparity is due to socioeconomic factors; however interaction of social and environmental factors can also modulate biological factors. A classic example is the protective effect that lactation has in preventing breast cancer in women. Several studies have shown how social factors, race, ethnic differences and socioeconomic status affect initiation, frequency, and duration of breastfeeding practices of mothers. These factors also affect a mother's decision whether or not to breastfeed and for how long she will breastfeed. Epidemiological data have shown that pregnancy and lactation at early age in humans reduces the risk of breast cancer. Nevertheless, the mechanism of this protective effect in humans is unknown. Studies in mice and rats have shown that lactation stimulates the expression of intracellular fatty-acid binding proteins (FABPs). Different FABPs (1-9) are expressed in specific tissues such as heart, brain, liver, etc. FABP3 expression is significantly increased in breast tissue of lactating rats and its expression regulates the protective effect initiated by lactation. FABP3 is also detected in human breast tissue and it is known as mammary-derived growth inhibitor (MDGI) because it has a strong inhibitory effect on cell proliferation. Well established is also the fact that FABPs have a compensatory relationship, i.e., levels of x-FABP increase when y-FABP is decreased. Therefore, since FABP3 inhibits breast cell proliferation, we reasoned that differential expression of this protein in breast tissues will correlate with breast cancer progression. Thus, we hypothesize that AA women will have lower levels of FABP3 since lactation rates among AA women are the lowest among CA, Hispanic (HA) and Asian American women. Similarly, we reasoned that FABP5 levels (also detected in breast) will be higher in tissues from AA women to compensate for the decrease in FABP3. Therefore we propose to assess the expression of these FABPs in paired normal/tumor BC tissues from AA and CA (obtained from Human Cooperative Tissue Network) to determine if lower expression of FABP3/higher expression of FABP5 among AA women is associated with the disparity in BC progression observed between AA and CA BC patients. To characterize the potential mechanisms associated with the regulation of FABP3 and FABP5 we will also use cell lines established from CA and AA patients obtained from ATCC. Protein levels of FABPs will be assessed by Western blotting, Elisa Assays and confocal immunofluorescence. mRNA levels will be assessed by quantitative rt-PCR. Since lactation is regulated by prolactin and IGF-II, we will also determine how these proteins regulate FABPs and cellular differentiation of the BC cell lines established from AA and CA women. If successful, our studies will provide much needed information about the mechanisms involved in the protective effect lactation induces in the breast and will potentially offer new tools for preventive breast cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is second only to lung cancer in terms of cancer-related death, and therefore, reducing the incidence of breast cancer is a critical health objective. African-American women have been shown to suffer from disproportionately high levels of breast cancer death compared to Caucasian women. In addition to socioeconomic concerns, biological factors such as differences in the expression of FABPs may contribute to this survival disparity. Our studies will provide much needed information about the mechanisms involved in the protective effect lactation induces in the breast and will potentially offer new tools for preventive breast cancer treatment.